New Insights into Connection of Nucleolar Functions and Cancer.

The nucleolus is an intranuclear membrane-less organelle. It is involved in ribosome biogenesis and protein synthesis. When the demand for protein synthesis increases in cell growth and proliferation (e.g., tumors), the cell upregulates ribosome biogenesis. Changes in nucleolar size and number have been recognized as known features of many tumor types. Recent evidence suggests that overproduction of ribosome, decreased ribosome biogenesis, and quantitative and qualitative changes in the nucleolus function, may result in oncogenesis. Today, it is clear that the nucleolus is involved in processes other than ribosome biogenesis. Other functions of the nucleolus include detecting and responding to endogenous and exogenous stress, maintaining genome stability, and regulating cell cycle progression, telomere function, cellular senescence, gene expression, and chromatin structure. Alterations in many of these fundamental nucleolar processes may contribute to the formation of cancer cell phenotypes. This phenomenon suggests that normal nucleolar functions are a safeguard against the development of malignancies and have potential therapeutic effects, as reported in non-small-cell lung carcinoma and other malignancies.


INTRODUCTION
The connection between the nucleolus and cancer has been a subject of research since the 19 th century. Giuseppe Traditionally, the nucleolus has been known as a coordinator of ribosomal biogenesis and protein production and may overreact during tumorigenesis.
Recently, knowledge about ribosome biogenesis and non-ribosomal functions has increased. Multiple studies have clearly shown that the nucleolus has many other functions, either ribosomal or non-ribosomal, including a role in cancer development (2). In this study, we briefly discuss recent findings on nucleolar connection to neoplastic transformations. For this purpose, we searched Google Scholar, Scopus, and Medline databases and relied on our experience to briefly discuss the established activities of the nucleolus in cancer.

Nucleolus
In eukaryotic cells, the nucleolus is an intranuclear membrane-less organelle. It is visible in the interphase of cell division via light microscopy. Among nuclear components, the nucleolus takes up to 25% of the nuclear  (8,9).

Ribogenesis
Traditionally, the main function of the nucleolus is ribosome biogenesis, which is a complex molecular machine responsible for protein production. Its major function is translation of mRNA into a variety of proteins. Accordingly, the produced ribosomes act as central players in mRNA translation into proteins (6,7,10,11).
Because of the crucial role of the nucleolus in ribosome biogenesis, it can actively determine the metabolic condition of a cell. In morphology, the size of the nucleolus is positively correlated with rRNA synthesis, which is related to cell growth and metabolism. This nucleolar change can be observed by light microscopy after silver staining (AgNOR) (12,13).

New insights into nucleolar function
For a long time, ribosome biogenesis in protein synthesis was considered as the only function of the nucleolus. However, in the past two decades, the role of the nucleolus in cellular function has been greatly recognized. Researchers have reported that the nucleolus function is not simply ribosome production, and pathologists identified a subnuclear structure, responsible for changes in the nucleolus size and shape in cancer cells (14). Today, it is believed that the nucleolus is a key controller of many cellular processes, which are fundamental to normal cell homeostasis. In addition, its dysregulation can be the target of many human diseases.
Previously, the nucleus was considered as the brain of the cell, while today, it is regarded as the brain of the nucleus (2,4,7,14,15

Gene stability
The nucleolus promotes gene stability.

Connection of nucleolar function with cancer
The nucleolus connection with cancer can be viewed from two perspectives (intermingling may also happen): • Changes in the nucleolus are a consequence of neoplastic transformation (1, 2).
• Functional nucleolar dysregulation by any reason is a risk factor for developing cancer (3,4,26).
The nucleolus, as a major contributor to ribosome production, is associated with cell cycle regulation in several subtle ways. One of these ways is the surveillance system. When rRNA synthesis or processing is impaired, the system reacts promptly, halting cell cycle progression.
Conversely, the nucleolus acts as the first responder to

Anti-cancer functions
Increase of rDNA transcription has been shown to be a